Defibrillation by electric shock is the only effective therapy for sudden cardiac death. However, defibrillation has a significant side effect, contributing to morbidity associated with the therapy. This effect is electroporation: strong electric field induced rupture of sarcolemmal membrane. Electroporation is believed to be responsible for clinical post shock depression of cardiac electrical and mechanical function, metabolic inhibition, bradieardia, complete heart block and increased pacing thresholds. On the other hand, electroporation is frequently a method of choice for delivery of large molecules across sarcolemma, a key in the success of future molecular medicine. Despite clear importance of electroporation, little is known about spatiotemporal mechanisms of development of eleetroporation and its consequences in complex three-dimensional tissue structure of the intact heart. Most striking puzzle is the existence of experimental evidence for both pro- and anti- arrhythmic effects of electroporation. We will investigate the mechanisms of electroporation with the following specific aims: 1. To investigate the spatial mechanisms of development of electroporation in complex 3D structure of the heart, using three approaches: (a) in vitro fluorescent imaging of effects of electric shocks in normal and infarcted rabbit hearts, (b) in numero anatomically accurate active bidomain computer modeling of electroporation, and (c) histological studies of electroporation and tissue damage with Propidium lodide. 2. To investigate the cellular mechanisms of electroporation in normal and infarcted rabbit hearts, including the effect of surfactants and ion channel modulators in the development of cellular response during electroporating shocks. 3. To investigate the role of electroporation in pro- and anti-arrhythmic response to strong electrical stimulation in vitro and in numero. We will investigate the role of electroporation in post-shock conduction abnormalities, in shock-induced vulnerability, in defibrillation, and in post-shock arrhythmogenesis of focal and reentrant nature. 4. To investigate the possibilities of designing electrode configurations and shock waveforms that will allow reduction of electroporation and irreversible tissue damage during defibrillation. Successful completion of the aims will help to enhance our understanding of basic mechanisms of electroporation in intact hearts. This new knowledge will help to reduce the side effects of defibrillation, which is likely to enhance safety and efficacy of defibrillation therapy of sudden cardiac death.